Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
  • C07D213/77—Hydrazine radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the invention relates to new polycyclic polyazaheterocycles and their acid addition salts, processes for their preparation and pharmaceutical preparations containing them.
• R 1 and R 2 independently of one another are hydrogen, lower alkyl or hydroxy-lower alkyl, or together lower alkylene or ethyleneoxyethylene, ethyleneazaethylene or N-lower alkyl or N- (2-hydroxy-lower alkyl) ethyleneazaethylene
• R 3 is hydrogen or a lower aliphatic or saturated, lower cycloaliphatic Hydrocarbon radical or unsubstituted or substituted phenyl
• R 4 and R 5 is hydrogen or lower alkyl
• Ar is an unsubstituted or substituted benzo or pyrid radical.
• a benzo or pyrid radical is understood to mean a divalent radical which, together with the two adjacent carbon atoms, forms a benzene or pyridine ring.
• the invention also relates to the acid addition salts of the compounds of the general formula I, in particular the pharmaceutically acceptable acid addition salts of compounds of the general formula I.
• lower and lower radicals are understood above and below to mean those which contain at most 7 and preferably at most 4 carbon atoms.
• Lower alkyl R 1 and / or R 2 is, for example, ethyl, propyl, isopropyl, butyl or isobutyl and especially methyl.
• the hydroxy is in the higher position than 1, and such residues are, for example, 2- or 3-hydroxypropyl, 2-, 3- or 4-hydroxybutyl and especially 2-hydroxyethyl.
• R 1 and R 2 together mean, for example, ethylene, trimethylene, hexamethylene and above all tetramethylene or pentamethylene, or correspondingly branched, ie lower alkylated, in particular methylated radicals, such as 1,4-dimethyltetramethylene or 3,3-dimethylpentamethylene.
• the lower alkyl in ethyleneazaethylene is, for example, ethyl, propyl, isopropyl and especially methyl
• the 2-hydroxy lower alkyl is, for example, 2-hydroxypropyl and especially 2-hydroxyethyl.
• R 3 is lower alkyl, lower alkenyl or lower alkynyl with at most 7 and preferably at most 4 carbon atoms.
• R3 as lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, 1-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, heptyl, isoheptyl, 1- Methylhexyl or 1-propylbutyl, as lower alkenyl, especially those with 3 to 4 carbon atoms, for example allyl, 1-methylallyl, 2-methylallyl, 2-butenyl or 3-butenyl, and as lower alkynyl, for example 2-propynyl or 2-butynyl.
• R 3 is in particular cycloalkyl, lower alkylcycloalkyl or cyeloalkylnie deralkyl each having a maximum of 7 carbon atoms, such as cyclopentyl, cyclohexyl, cycloheptyl or 2- or 4-methylcyclohexyl, or cyclopropylmethyl, cyclopentylmethyl, 2-cyclopentylethyl or cyclohexylmethyl.
• Substituted phenyl R 3 is, for example, phenyl which is mono- or polysubstituted by halogen to atom number 35, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, cyano and / or nitro.
• the ring nitrogen atom can be in any of the 4 possible positions, in particular it is in the 4 position and especially in the 2 position to the ring carbon atom which is connected to the nitrogen atom of the pyrazine ring substituted by R 3 .
• Ar is therefore the pyridone radical, based on the central pyrazine ring, in particular the pyrido [4,3-e] - and especially the pyrido [2,3-e] radical.
• Substituents of a benzo or pyrid radical Ar are, for example, halogen to atomic number 35, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, cyano or nitro.
• the substituent of phenyl R 3 and / or the halogen present as Ar is fluorine, bromine or, above all, chlorine, lower alkyl, for example ethyl, propyl, isopropyl, butyl or tert-butyl and in particular methyl, lower alkoxy, for example ethoxy, propoxy, isopropoxy, Butoxy or isobutoxy, and in particular methoxy, and lower alkylthio, for example ethylthio, propylthio, isopropylthio, butylthio and in particular methylthio.
• Lower alkyl R 4 is, for example, isopropyl or preferably primary lower alkyl, such as ethyl, propyl, isobutyl and especially methyl and lower alkyl
• R 5 is preferably one of the aforementioned primary lower alkyls, especially methyl in addition to methyl R 4 .
• Particularly suitable acid addition salts of compounds of the formula I are pharmaceutically acceptable acid addition salts.
• Such as the free compounds of general formula I can optionally be used as active ingredients for pharmaceutical preparations will. Examples include the addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid and emetic acid, mandic acid, salicylic acid, mandic acid, cited acid.
• the compounds of general formula I and their acid addition salts have valuable psychopharmacological properties.
• they have an antagonistic effect on resotherin-induced hypothermia, for example in the case of intraperitoneal or oral administration to the rat, [cf. Benz and Waser, drug research. 21 (5) 654 (1971)] in the dose range from 10 to 100 mg / kg, and compared to the ptosis induced by tetrabenazine with intraperitoneal or oral administration to the rat [cf. Rubin et al., J. Pharmacol. exptl. Ther. 120, 125 (1957)] in the dose range from 3 to 100 mg / kg.
• the ED 50 of 4,5-dihydro-2 - [(dimethylamino) methyl] -5-phenyl-1,2,4-triazolo [1,5-a] quinoxaline hydrochloride in the second test is 3-10 mg / kg per os and 10 mg / kg ip.
• the compounds of the general formula I like the aforementioned anxiolytic effect after oral administration of doses from 1 mg / kg.
• the compounds of the general formula I In contrast to the rather negatively inotropic and positively chronotropic effect of some known antidepressants, such as imipramine, the compounds of the general formula I, like the aforementioned, have a weakly positive inotropic and weakly negatively chronotropic effect on the isolated guinea pig atrium. The toxicity of the compounds of the general formula I is low compared to the desired pharmacological effects. These properties characterize the compounds of the general formula I as antidepressants and anxiolytics, which can be used for the treatment of depression.
• R 3 has a lower aliphatic or a saturated lower cycloaliphatic hydrocarbon radical or unsubstituted or phenyl substituted by halogen to atom number 35, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, cyano or nitro and Ar an unsubstituted or substituted by substituents of the aforementioned type Pyrido [2,3-e] radical and R 4 and R 5 have the meaning given under formula I, and their acid addition salts, in particular the pharmaceutically acceptable acid addition salts.
• the invention particularly relates to compounds of the general formula I in which R 1 is lower alkyl, R 2 is hydrogen or lower alkyl, or R 1 and R 2 together are lower alkylene, R 3 is phenyl unsubstituted or substituted by halogen to atom number 35 or lower cycloalkyl and Ar is an unsubstituted one or benzo or pyrido [2,3-e] radical substituted by halogen to atom number 35, and R 4 and R 5 have the meaning given under the formula I, and their acid addition salts, in particular the pharmaceutically acceptable acid addition salts.
• the invention relates in particular to compounds of the general formula I in which R 1 is lower alkyl, in particular methyl, R 2 is hydrogen or lower alkyl, in particular methyl, or R 1 and R 2 together are lower alkylene, in particular tetramethylene, R 3 is unsubstituted or by halogen to atom number 35 , in particular chlorine, substituted phenyl, and Ar is an unsubstituted or substituted by halogen to atom number 35, in particular chlorine-substituted benzo radical or the pyrido [2,3-e] radical, R 4 has the meaning given under formula I and R 5 is hydrogen or Means methyl, and their acid addition salts, especially the pharmaceutically acceptable acid addition salts.
• the invention relates primarily to compounds of the general formula I in which R is methyl, R 2 is hydrogen or methyl, R 3 is phenyl, R 4 is hydrogen or methyl, R 5 is methyl or especially hydrogen, and Ar is benzo or pyrido [2 , 3-e] residue means, and their acid addi tion salts, especially the pharmaceutically acceptable acid addition salts.
• Suitable reactions for the reactions according to a) are as reactive esters of compounds of the general formula II, for example esters of organic sulfonic acids, such as lower alkanesulfonic acid esters or arenesulfonic acid esters, e.g. Methanesulfonic acid ester or benzenesulfonic acid or p-toluenesulfonic acid ester, or halides, especially bromides, chlorides or iodides.
• the reactions are carried out, for example, in an inert organic solvent at temperatures from about 0.degree. C. to about 100.degree. C. or the boiling point of the solvent used, if this is lower than 100.degree.
• the reduction of compounds of the general formula IV according to b) can be carried out, for example, using a lower alkyl aluminum hydride, such as diisobutyl aluminum hydride, e.g. in an aromatic hydrocarbon such as toluene at temperatures between about -10 ° C and room temperature, or by means of lithium aluminum hydride or diborane in an ethereal solvent such as diethyl ether or tetrahydrofuran, e.g. at temperatures between room temperature and about 55 ° C or boiling point of the solvent, if this is below 55 ° C, are carried out.
• a lower alkyl aluminum hydride such as diisobutyl aluminum hydride
• an aromatic hydrocarbon such as toluene
• an ethereal solvent such as diethyl ether or tetrahydrofuran
• a radical R 3 which is different from hydrogen and has at least one hydrogen atom on the bonding carbon atom and is therefore neither aromatic nor bound via a quaternary carbon atom, into a compound of the general formula I in which R 3 is hydrogen, according to c), in particular by reaction of a the latter compounds with a reactive ester of a secondary or preferably primary lower alkanol, lower alkenol or lower alkynol, or a cycloalkanol with 5 to 7 carbon atoms or a preferably primary cycloalkyl lower alkanol with 4 to 7 carbon atoms.
• the corresponding reactive esters used are hydrohalic acid esters, such as chlorides or, in particular, bromides or iodides, or esters with organic sulfonic acids, such as lower alkanesulfonic acid or arenesulfonic acid esters, for example methanesulfonic acid ester or benzenesulfonic acid or p-toluenesulfonic acid ester, of methanol, ethanol, propanol, isopropanol, butanol , isobutanol, allyl alcohol, 2-methylallyl, 2-propynol, cyclopentanol, cyclohexanol, cycloheptanol, cyclopropyl, cyclobutyl, cyclopentyl or Cyclohe h ylmethanol or 2-cyclopentyl ethanol.
• hydrohalic acid esters such as chlorides or, in particular, bromides or iodides
• the reaction can be carried out in an inert organic solvent or diluent and, for example, at temperatures between about 0 ° C. and 100 ° C., in particular between room temperature and about 80 ° C. or the boiling point of the solvent, if this is below 80 ° C., in the presence of a basic condensing agent, for example an alkali metal, alkali metal amide or hydride, or an alkali metal lower alkoxide, such as sodium or potassium methoxide, ethoxide or tert-butoxide.
• a basic condensing agent for example an alkali metal, alkali metal amide or hydride, or an alkali metal lower alkoxide, such as sodium or potassium methoxide, ethoxide or tert-butoxide.
• a primary radical R 3 can also be introduced, for example, by a two-stage reaction sequence, by first acylating the compound of the general formula to the corresponding compound with the acyl radical of a lower alkanoic acid or cycloalkyl-lower alkanoic acid with at most 7 carbon atoms in the 5-position and the latter compound using a hydride reducing agent reduced in analogy to method b).
• the introduction of one or two residues R other than hydrogen . and / or R 2 into a compound of the general formula I in which at least one of the symbols R 1 and R 2 is hydrogen can, for example, by reacting a corresponding compound of the general formula I with the equimolar or, if appropriate, at least double molar amount of a reactive ester, for example, a hydrohalic acid ester, such as a chloride or in particular bromide or iodide, or an ester with an organic sulfonic acid, for example a lower alkanesulfonic acid or arenesulfonic acid ester, such as methanesulfonic acid ester or benzenesulfonic acid or p-toluenesulfonic acid ester of a non-tertiary lower alkanol or a corresponding mono- or Diesters of a lower alkanediol, for example a corresponding ester of methanol, ethanol, propanol, is
• a further possibility for introducing radicals R 1 and / or R 27 other than hydrogen into compounds of the general formula I suitable for this purpose is to implement such Compounds with oxo lower alkanes, such as formaldehyde, acetaldehyde, acetone, 2-butanone or 3-pentanone under reducing conditions, for example in the presence of formic acid at temperatures from about 60 ° C. to about 100 ° C. or in an inert organic solvent in the presence of hydrogen and a conventional hydrogenation catalyst, for example a noble metal catalyst, such as palladium on carbon or an alkaline earth metal carbonate, or platinum oxide, or Raney nickel, at room temperature and normal pressure or moderately elevated temperatures and pressures.
• oxo lower alkanes such as formaldehyde, acetaldehyde, acetone, 2-butanone or 3-pentanone
• a conventional hydrogenation catalyst for example a noble metal catalyst, such as palladium on carbon or an alkaline earth metal carbonate, or platinum
• the compounds of the general formula II are also new substances.
• Ar is a benzo radical and R5 are hydrogen
• R 3 and R 4 have the meaning given under the formula I, for example, o- in the amino group optionally substituted in accordance with the definition of R 3 and optionally in the benzene ring Nitroanilines run out.
• a suitable protective group such as a lower alkoxycarbonyl group, for example the ethoxycarbonyl group, is first introduced by successive action of sodium hydride and ethyl chloroformate in dimethylformamide, and the nitro group in the product obtained is reduced to the amino group in a conventional manner, for example by means of hydrogen in the presence of Raney nickel .
• the reduction product is converted into the corresponding diazonium chloride by solution in a hydrochloric acid / acetic acid mixture and addition of sodium nitrite solution and the latter with a (2-chloro-lower alkanamido) -malonic acid lower alkyl ester, such as the diethyl ester, for the corresponding azo compound, for example the corresponding [2- ( N-alkoxycarbonyl-NR -amino) -phenylazo] - (2-chloro-lower alkanamido) -malonate, coupled.
• Hydrobromic acid in the heat, for example at about 90 ° C; cyclized to the corresponding 4-R4 5-R3-4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline-2-carboxylic acid.
• This can contain substituents in the benzene ring, ie in one of the positions 6, 7, 8 or 9, provided that an NR 3 -2-nitroaniline correspondingly substituted in the benzene ring was assumed.
• the carboxylic acid obtained can finally, directly or after esterification, for example conversion into the methyl ester by boiling with methanol and hydrochloric acid, using a hydride reducing agent, for example treatment with sodium borohydride in a mixture of methanol and tetrahydrofuran, to give the corresponding 4-R 4 -5-R 3 -4,5-dihydro- [1,2,4] -tri-azolo [1,5-a] quinoxaline-2-methanol of the general formula II can be reduced.
• a hydride reducing agent for example treatment with sodium borohydride in a mixture of methanol and tetrahydrofuran
• the latter can be converted in the customary manner into the reactive ester desired for the reaction according to a), for example by reaction with methanesulfonyl chloride in the presence of a suitable base, for example triethylamine, in an inert organic solvent in the corresponding methanesulfonic acid ester, or by reaction with phosphorus tribromide in an inert one organic solvent in the corresponding bromide, ie the corresponding 2- (bromomethyl) compound.
• a suitable base for example triethylamine
• phosphorus tribromide in an inert one organic solvent in the corresponding bromide, ie the corresponding 2- (bromomethyl) compound.
• the amino compound mentioned is converted into the corresponding diazonium chloride in a conventional manner and the latter with a (2-chloro-lower alkanamido) - malonic acid lower alkyl esters, such as the diethyl ester or dimethyl ester, are coupled to the corresponding (2-chloro-lower alkanamido) - (2-chloro-3-pydridylazo) -malonic acid lower alkyl ester.
• a (2-chloro-lower alkanamido) - malonic acid lower alkyl esters such as the diethyl ester or dimethyl ester
• the latter is reacted with ammonia or a primary amine of the formula R 3 -NH 2 , optionally in the presence of a catalytic to double-molar amount of an alkali metal iodide, in the corresponding 4-R 4 -5-R 3 -4,5-dihydro-pyrido [2 , 3-b] - [1,2,4] triazolo [1,5-d] pyrazine-2-carboxylic acid, and the latter is reduced analogously to the aforementioned reaction sequence, preferably after esterification, to the corresponding compound of the general formula II and this into one suitable reactive ester transferred.
• the starting materials of the general formula IV in which X is oxygen and n is zero, for the reduction according to b) are also new. They can be prepared in a manner known per se from the corresponding carboxylic acids or their functional derivatives mentioned above, for example the lower alkyl esters likewise already mentioned or for example also the corresponding acid chlorides, by reaction with amines of the general formula III.
• Such raw materials of general my formula IV, in which R 4 and R 5 are each lower alkyl, in particular methyl, is preferably made from corresponding compounds with lower alkyl as R 4 and hydrogen as R 5 by introducing lower alkyl R 5 analogously to the introduction of lower alkyl R 5 mentioned above the esters corresponding to the amides of the general formula IV.
• the new compounds can, depending on the choice of starting materials and procedures, in the form of one of the possible stereoisomers or as a mixture thereof, e.g. depending on the number of asymmetry centers as pure optical isomers, i.e. optical antipodes or as racemates, and in the case of diastereoisomerism also as racemate mixtures.
• Racemic mixtures obtained can be separated into the pure racemates in a known manner on account of the physico-chemical differences in the constituents, for example by chromatography and / or fractional crystallization.
• Racemates obtained can be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms, or by reacting an end product with an optically active acid which forms salts with the racemic base and separating the obtained in this way Salts, e.g. due to their different solubilities, in the diastereomers, from which the antipodes can be released by the action of suitable agents.
• the more effective of the two antipodes is advantageously isolated.
• Free compounds of formula I obtained can be converted into acid addition salts in a manner known per se, i.a. by treatment with the appropriate acid, usually in the presence of a solvent or diluent.
• Acid addition salts obtained can be converted into the free compounds in a manner known per se, e.g. by treating with a base such as an alkali metal hydroxide or a basic ion exchanger.
• a base such as an alkali metal hydroxide or a basic ion exchanger.
• the compounds, including their salts, can also be obtained in the form of their hydrates or include the solvent used for the crystallization.
• the invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses an optical antipode and / or a starting material in the form of a salt instead of a racemate, or in particular forms under the reaction conditions.
• the pharmaceutical preparations according to the invention contain e.g. from about 10% to about 95%, preferably from about 20% to about 90%, of at least one active ingredient according to the invention together with at least one pharmaceutical carrier or auxiliary.
• Pharmaceutical preparations according to the invention are e.g. those in unit dose forms, such as coated tablets, tablets, capsules or suppositories, and also ampoules. 10 to 500 mg, and preferably 25-250 mg of active ingredient.
• the pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. manufactured using conventional mixing, granulating, coating, solution or lyophilization processes.
• compositions for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, into tablets or dragee cores after adding suitable auxiliaries .
• suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch paste, e.g.
• Dragee kernels are provided with suitable, possibly gastric juice-resistant coatings, whereby, among other things, Concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. Colorants or pigments, e.g. for identification or for labeling different doses of active ingredient.
• Concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate.
• Colorants or pigments e
• capsules made of gelatin as well as soft, closed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol.
• the capsules can Active ingredient in the form of granules, for example in a mixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers.
• the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.
• suppositories into consideration consist of a combination of the active ingredient with a suppository base.
• Suitable suppository bases are e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
• Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material; as basic materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.
• aqueous solutions of an active ingredient in water-soluble form e.g. a water-soluble salt
• further suspensions of the active ingredient such as corresponding oily injection suspensions
• suitable lipophilic solvents or vehicles such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. Contain sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.
• the invention also relates to the use of the compounds of the general formula I and their pharmaceutically acceptable acid addition salts as medicaments, in particular as antidepressants or anxiolytics, preferably in the form of pharmaceutical preparations.
• the dosage depends on the warm-blooded species, the age and the individual condition of the warm-blooded animal to be treated, and on the appli from cation.
• the doses administered per day are between approximately 1 and approximately 100 mg / kg and preferably, for example for warm-blooded animals of approximately 70 kg body weight, between approximately 3 and approximately 50 mg / kg.
• Example 1 To the suspension of 5.00 g (0.018 mol) of 5-phenyl-4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline-2-methanol in 180 ml abs . Methylene chloride and 3.64 g (0.036 mol) of triethylamine are added dropwise under nitrogen at -10 ° to 3.10 g (0.027 mol) of methanesulfonic acid chloride in the course of 5 minutes.
• the methanesulfonic acid ester thus obtained is immediately reacted further without further purification by adding an ice-cold mixture of 15.0 ml (0.11 mol) of 33% ethanolic dimethylamine solution and 15 ml of ethanol and stirring the reaction mixture for one hour. Then it is evaporated in vacuo and the residue is dissolved in ethyl acetate and 1-n. Potassium bicarbonate solution. The aqueous phase is separated off and extracted twice more with ethyl acetate. The combined organic extracts are washed three times with water and once with saturated sodium chloride solution and dried over sodium sulfate.
• Example 2 The from 8.70 g (0.0313 mol) of 5-phenyl-4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline-2-methanol and 5.92 g (0.051 mol) of methanesulfonic acid chloride prepared according to Example 1 crude methanesulfonic acid ester is stirred after the addition of 24 ml (0.188 mol) of 33% ethanolic methylamine solution and 24 ml of ethanol for one hour at room temperature. The reaction mixture is then evaporated in vacuo and the residue is dissolved in ethyl acetate and 1-n. Potassium bicarbonate solution.
• the aqueous phase is separated off and extracted twice more with ethyl acetate.
• the combined organic extracts are washed 3 times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo.
• Example 3 A suspension of 22.50 g (0.066 mol) of 2- (bromomethyl) -5-phenyl-4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline in 225 ml Isopropanol and 45.30 ml (0.33 mol) of 33% ethanolic dimethylamine solution are stirred under nitrogen at room temperature for two hours. Then it is evaporated in vacuo and the residue is dissolved in ethyl acetate and 1-n. Potassium bicarbonate solution. The aqueous phase is separated off and extracted twice more with ethyl acetate. The combined organic extracts are washed three times with water and once with saturated sodium chloride solution and dried over sodium sulfate.
• Example 4 In the suspension of 1.20 g (0.0037 mol) of N, N-dimethyl-5-phenyl-4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline -2-carboxamide in 180 ml abs. Toluene is added dropwise at 2.degree. Under nitrogen with 9.40 ml (0.011 mol) of a 1.2 molar solution of diisobutylaluminum hydride in toluene within 15 minutes. The resulting clear yellow solution is stirred for a further hour at 5 °, then 5 ml of isopropanol are added dropwise to the reaction mixture and poured onto an ice-water mixture.
• Example 5 Analogously to Example 1, starting from 9.30 g (0.0297 mol) of 5- (4-chlorophenyl) -4,5-dihydro- [1,2,4] -triazolo [1,5-a] -quinoxaline-2-methanol over its crude methanesulfonic acid ester using 40.7 ml (0.297 mol) of 33% ethanolic dimethylamine solution the 2 - [(dimethylamino) methyl] -5- (4-chlorophenyl) -4.5- dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline hydrochloride which, after recrystallization from methylene chloride / isopropanol, sinters at 230 ° and melts at 248-251 ° with decomposition.
• Example 2 Analogously to Example 1, starting from 8.0 g (0.026 mol) of 7-chloro-5-phenyl-4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline-2-methanol About its crude methanesulfonic acid ester using 25.6 ml (0.218 mol) of 33 Z-ethanolic dimethylamine solution, the 7-chloro-2 - [(dimethylanino) methyl] -5-phenyl-4,5-dihydro- [1,2 , 4] -triazolo [1,5-a] -quinoxaline hydrochloride, which sinters from 220 ° after recrystallization from methylene chloride / ethyl acetate and melts at 228-232 ° with decomposition.
• Example 2 Analogously to Example 1, starting from 16.50 g (0.0432 mol) of 8-chloro-5- (2,4-dichlorophenyl) -4,5-dihydro- [1,2,4] -triazolo [1,5 -a] -quinoxaline-2-methanol over its crude methanesulfonic acid ester using 59.0 ml (0.432 mol) of 33% ethanolic dimethylamine solution, the 8-chloro-2 - [(dimethylamino) methyl] -5- (2, 4-dichlorophenyl) -4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline hydrochloride, which after recrystallization from methylene chloride / isopropanol from 282 ° melts under decomposition.
• N- (2,3-dimethylphenyl-2) is obtained in a completely analogous manner, starting from 117.00 g (0.830 mol) of 1-fluoro-2-nitrobenzene and 222.00 g (1.826 mol) of 2,3-dimethylaniline in 585 ml of dimethyl sulfoxide -nitroaniline of mp. 118-120 ° after recrystallization from methylene chloride / hexane.
• Example 6 To the suspension of 10.00 g (0.0358 mol) of 5-phenyl-4,5-dihydropyrido [2,3-e] [1,2,4] triazolo [1,5-a] pyrazine-2-methanol in 350 ml abs. Methylene chloride and 7.24 g (0.072 mol) of triethylamine are added dropwise at ⁇ 8 to -5 ° 6.15 g (0.054 mol) of methanesulfonic acid chloride within 10 minutes. The clear, yellow reaction solution is stirred for 90 minutes at room temperature and then washed three times with ice water and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo.
• the methanesulfonic acid ester of 5-phenyl-4,5-dihydro-pyrido [2,3-e] - [1,2,4] triazolo [1,5-a] pyrazine-2-methanol is obtained as a light yellow crystalline residue and without Further purification was immediately implemented by adding an ice-cold mixture of 35.4 ml (0.26 mol) of 33% ethanolic dimethylamine solution and 35 ml of ethanol, and the reaction mixture was closed and stirred for 3 hours. Then it is evaporated in vacuo and the residue is dissolved in ethyl acetate and 1-n. Potassium bicarbonate solution. The aqueous phase is separated off and extracted twice more with ethyl acetate.
• Example 7 The from 10.00 g (0.036 mol) of 5-phenyl-4,5-dihydro-pyrido [2,3-e] [1,2,4] triazolo [1,5-a] pyrazine-2 -methanol and 6.15 g (0.054 mol) of methanesulfonic acid chloride crude methanesulfonic acid ester prepared according to Example 6 are stirred after adding 88 ml (0.934 mol) of 33% ethanolic methylamine solution and 20 ml of ethanol overnight at room temperature. The reaction mixture is then evaporated in vacuo and the solid residue is dissolved in ethyl acetate and 1-n. Potassium bicarbonate solution.
• the aqueous phase is separated off and extracted again with ethyl acetate.
• the combined extracts are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.
• the residue is dissolved in 200 ml of ethanol and mixed with a saturated ethanolic fumaric acid solution until the pH of a sample with water is 4. After 5 hours, the precipitated crystals are filtered off and recrystallized twice from ethanol.
• Example 9 To the solution of 8.00 g (0.027 mol) of 4-methyl-5-phenyl-4,5-dihydro- [1,2,4] -triazolo [1,5-a] quinoxaline-2-methanol in 270 ml abs. Methylene chloride and 5.50 g (0.055 mol) of triethylamine are added dropwise under nitrogen at 0 ° to 4.70 g (0.041 mol) of methanesulfonic acid chloride within 5 minutes. After stirring at 0 to 4 ° for one hour, the clear reaction mixture is poured onto an ice-water mixture, the organic phase is separated off and the aqueous phase is extracted again with methylene chloride. The extracts are washed twice with ice-cold water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo.
• the crude hydrochloride formed is filtered off and washed with ethyl acetate. Then it is dissolved in 50 ml of methylene chloride and 100 ml of ethyl acetate. After the methylene chloride has been evaporated off in vacuo at 40 °, the desired hydrochloride crystallizes out again. The mixture is left to stand in the refrigerator for 2 hours, then the crystals are filtered off and washed with ethyl acetate.
• Example 10 To the solution of 7.70 g (0.022 mol) of N, N, 4,4-tetramethyl-5-phenyl-4,5-dihydro [1, 2,4] triazolo [1,5-a ] quinoxaline-2-carboxamide in 1100 ml abs. Toluene is added dropwise at 0 to 2 ° under nitrogen, 55.40 ml (0.066 mol) of a 1.2 molar solution of diisobutylaluminum hydride in toluene within 20 minutes.
• reaction mixture is stirred for a further hour at 5 °, then 15 ml are added dropwise Isopropanol and then 160 ml of ice-cold water and so much concentrated sodium hydroxide solution until the pH 11 is reached.
• the organic phase is separated off and the aqueous phase is extracted again with toluene.
• the combined organic extracts are washed twice with 2-n.
• Sodium hydroxide solution washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.
• the residue of honey-like consistency is dissolved in ethyl acetate and the solution is chromatographed on a column of 180 g of silica gel first with 2 1 ethyl acetate and then with 3 1 methylene chloride-methanol (95: 5).
• the fractions which contain the desired product are evaporated in vacuo, dissolved in ethyl acetate and mixed with ethereal hydrogen chloride solution with stirring until the pH 4 is reached. After stirring for one hour in an ice bath, the pure hydrochloride formed is filtered off and washed with ethyl acetate.
• Example 11 Tablets containing 100 mg of 2 - [(dimethylamino) methyl] -5-phenyl-4,5-dihydro- [1,2,4] triazolo [1,5-a] quinoxaline hydrochloride as active ingredient can, for example are produced in the following composition.
• the active ingredient is mixed with milk sugar, part of the wheat starch and with colloidal silica and the mixture is passed through a sieve.
• Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture is kneaded with this paste until a weak plastic mass has formed.
• the mass is passed through a sieve of approx. 3 mm mesh, dried and the dry granules are again passed through a sieve.
• the remaining wheat starch, talc and magnesium stearate are then mixed in.
• the mixture obtained is pressed into tablets of 250 mg with a notch (s).
• Example 12 Analogously to Example 11, tablets with a content of 50 mg of active ingredient each can be produced using 50 mg of 2 - [(dimethylamino) methyll-5-phenyl-4,5-dihydro- [1,2,4] -triazolo- [l, 5-a] quinoxaline and 100 mg lactose per tablet.
• Example 13 In order to produce 1000 capsules each with an active substance content of 100 mg, 100 g of 2 - [(dimethylamino) methyl] -5-phenyl-4,5-di-hydro- [1,2,4] -triazolo [1 , 5-a] quinoxaline hydrochloride with 173.0 g lactose, moisten the mixture evenly with an aqueous solution of 2.0 g gelatin and granulate it through a suitable sieve (eg sieve III according to Ph. Helv. V.). The granules are mixed with 10.0 g of dried corn starch and 15.0 g of talc and filled evenly into 1000 hard gelatin capsules of size 1.
• a suitable sieve eg sieve III according to Ph. Helv. V.

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